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From: TSS ()
Subject: Prion Toxicity: All Sail and No Anchor Adriano Aguzzi
Date: June 3, 2005 at 1:36 pm PST

##################### Bovine Spongiform Encephalopathy #####################

Prion Toxicity:

All Sail and No Anchor

Adriano Aguzzi

Within the past 2 years, our understanding

of the infectious particles

responsible for fatal neurological

conditions such as mad cow disease,

scrapie, and Creutzfeld-Jakob disease has

seen considerable progress (1). There is

now strong evidence that prions, the culprit

infectious particles, can be synthesized in

systems that are completely free of cellular

material (2, 3). This may essentially settle

the score as to the purely proteinaceous

nature of the infectious agent. As to the

march of prions toward the brain, or "neuroinvasion,"

a wealth of players has been

uncovered, as well as an intricate relationship

between immunological and nervous

compartments of the host organism (4, 5).

Still, the physiological function of PrPC, the

form of prion protein that cells normally

harbor, remains essentially mysterious.

Also, we do not understand how the infectious

form of the prion protein, a structurally

distorted form of its normal counterpart,

achieves brain damage. A tantalizing

inroad has now been made by Chesebro and

colleagues as to the latter question on page

1435 of this issue (6).

The causative agent of transmissible

spongiform encephalopathies (TSEs) such

as scrapie is PrPSc, a misfolded, proteaseresistant

version of the normal PrPC protein

(encoded by the Prnp locus in mice). PrPSc

forms orderly aggregates that often

progress into large extracellular deposits

commonly described as brain plaques. It is

argued that PrPSc multiplies by recruiting

and converting PrPC into further PrPSc. But

this hypothesis does not explain how infectious

prions proceed to induce the spongy

brain lesions of TSEs and, eventually,

extensive neuronal death. Curiously, PrPSc

itself is innocuous: When the brain of a

mouse lacking normal prion protein is

grafted with brain tissue replete with PrPC

and then subsequently exposed to infectious

prions, sizable amounts of PrPSc are

produced, yet the mouse fails to develop

TSE (7). So why aren't PrPC-deficient neurons

affected by the infectious agent?

Chesebro et al. have investigated this

question in a sophisticated model system.

During its early biogenesis, PrPC is directed

to the lumen of the endoplasmic reticulum,

thus entering the cellular secretory pathway.

A glycosylphosphatidylinositol (GPI)

lipid anchor is then added to its C terminus,

tethering the protein to the outer side of the

cell membrane. Chesebro et al. redacted a

Prnp transgene to remove the signal peptide

responsible for GPI anchoring. As a consequence,

the resulting GPI-negative transgenic

mice expressed a monomeric, soluble

secreted form of PrPC.

When infected with PrPSc, the GPI-negative

transgenic mice never developed clinical

prion disease. Quite surprisingly,

though, their brains were packed with

PrPSc plaques! Evidently, removal of the

GPI anchor abolished susceptibility to

clinical disease while preserving the competence

of the soluble PrPC molecule to

support prion replication. This interpretation

fits very nicely with the growing body

of evidence that normal prion protein may

function as a signaling molecule, just like

many other GPI-linked proteins. Altered

PrPC signaling may therefore be unhealthy

(see the figure). Indeed, cross-linking of

PrPC on the surface of hippocampal neu-

rons with antibodies sends the cells into

untimely demise (8). Hence, we are led to

wonder whether the damage wrought on

neurons by clustered PrPC proteins relates

to TSE neurodegeneration. If so, could the

mechanism by which prion infections lead

to brain damage be related to the normal

function of PrPC?

Mice lacking normal prion protein live a

healthy and long life without pathological

phenotypes, so loss of function of PrPC is

most certainly not a cause of brain damage in

TSE. Could any gain of function of PrPC trigger

disease pathogenesis? Morphological

findings would appear to depose against this

hypothesis as well. Although the clustering

of molecules at the cell surface is a common

way to initiate signaling, injecting antibodies

to PrPC into a mouse brain does not elicit

spongiosis. Conversely, ordered aggregation

is a crucial event in the formation of PrPSc

and may represent the true mechanism by

which infectivity is generated (9).

Chesebro et al.'s findings yield powerful

support for a link between the cell surface

topology of PrPSc and prion disease pathogenesis.

By disengaging PrPC from the cell

surface, the authors have effectively uncoupled

clinical disease from prion replication,

PrPSc formation, and its assembly into

higher order aggregates and the hallmark

brain plaques. It is almost unavoidable to

conclude that prion replication avails itself

of membrane-bound signal transducers to

elicit brain damage.

Another twist to Chesebro et al.'s story

relates to the structural requirements for

prion replication. In contrast to GPI-negative

mice, transgenic mice that express a

soluble dimeric version of PrPC do not

accumulate PrPSc in their brains or spleens

upon prion infection, nor do they develop

or transmit TSE (10). Instead, the soluble

dimeric form efficaciously competes with

endogenous PrPC and delays prion pathogenesis

in normal mice. In combination

with Chesebro et al.'s results, this indicates

that detachment of PrPC from the membrane

does not necessarily abolish its prion

replication competence. The soluble

dimeric form may act as a dominant-negative

form that sequesters PrPSc, rendering it

unavailable and thereby inhibiting disease


Brain extracts of prion-infected GPInegative

mice did not elicit plaque formation

when injected into other GPI-negative

mice. The importance of this failed

attempt at transmission is unclear, but

such a result may point to some kind of

def iciency in the prion replication

machinery of these transgenic mice.

For all the insight brought about by

Chesebro et al.'s findings, a central question

remains. Accruing evidence suggests

that signaling at the membrane involving

PrPC underlies TSE pathogenesis.

Infectious prions may damage the brain by

distorting signaling events that PrPC normally

controls. If that is true, the best way

to find out what exactly goes wrong in the

brains of prion-infected individuals may be

to sort out the normal function of PrPC. Yet

despite 13 years of availability of mice

lacking normal prion protein, progress

toward resolving the latter question has

been painstakingly slow. Although

Chesebro et al.'s work exemplifies the awesome

power of mouse transgenetics, a next

important step may consist of porting the

prion signaling system to simpler, genetically

tractable organisms such as worms,

flies, or fish, whose use is already having a

tremendous impact on the study of other

neurodegenerative diseases.


1. A. Aguzzi, C. Haass, Science302, 814 (2003).

2. J. Castilla, P. Saa, C.Hetz, C. Soto, Cell121, 195 (2005).

3. G. Legname et al., Science305, 673 (2004).

4. M. Prinz et al., Nature425, 957 (2003).

5. M. Heikenwalder et al., Science307, 1107 (2005);

published online 20 January 2005 (10.1126/


6. B. Chesebro et al., Science308, 1435 (2005).

7. S. Brandner et al., Nature379, 339 (1996).

8. L. Solforosi et al., Science303, 1514 (2004); published

online 29 January 2004 (10.1126/science.1094273).

9. J.T. Jarrett, P.T. Lansbury Jr., Cell73, 1055 (1993).

10. P. Meier et al., Cell113, 49 (2003).




Prion Toxicity:

All Sail and No Anchor

Adriano Aguzzi

The author is at the Institute of Neuropathology,

University Hospital of Zürich, CH-8091 Zürich,

Switzerland. E-mail:



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